1. Field of the Invention
The invention relates to anti-CEACAM6 antibodies and antibody fragments, nucleic acids encoding them, methods of their manufacture, and methods to treat cancer using these compounds.
2. Description of the Background
CEACAM6, carcinoembryonic antigen cell adhesion molecule 6 or CD66, is related to carcinoembryonic antigen (CEA) and both are members of the immunoglobulin superfamily of proteins. CEACAM6 is a cell surface oncogene which is composed of immunoglobulin-like (Ig-like) domains capable of homophilic and heterophilic interactions (Beauchemin N, et. al., Exp Cell Res. 252(2): 243-9, 1999; Kuroki, et. al. J Leukoc Biol. 70(4): 543-50, 2001). It is a 320 amino acid long cell surface GPI-linked glycoprotein comprised of 3 Ig-like C2 domains with a short C-terminal cytoplasmic tail. The expression profile of CEACAM6 in normal human tissues show moderate expression in a variety of epithelial tissue and myeloid cells. However, deregulated cell surface expression of CEA and CEACAM6 is observed in approximately 50% human cancers (25). An immunohistochemical study of human tissue expression of CEACAM6 showed intense staining on proliferating cells of hyperplastic polyps and adenomas when compared to normal colorectal mucosa (26). These observations represent some of the earliest molecular events in colonic epithelial cells that lead to colorectal cancer. However, deregulated cell surface expression of CEACAM6 is observed in ˜50% of human cancers, including colorectal and pancreatic cancer. Further, it has been demonstrated that de-regulated over-expression of CEACAM6 inhibits differentiation and apoptosis of cells when deprived of their anchorage to the extracellular matrix (ECM) (Ordoñez, et. al, Cancer Research, 60, 3419-3424, 2000), a process known as anoikis, which accompanies malignant transformation and strongly implicates CEACAM6 as an oncogene.
The utilization of therapeutic monoclonal antibodies (unconjugate or conjugated) for the treatment of human diseases including solid and hematological malignancies is well validated and established. Particularly useful for therapeutic applications are chimeric or humanized monoclonal antibodies due to their reduced immunological side effects. The efficacy and potency of this approach has been validated for Non-Hodgkin's Lymphoma (targeting CD20 antigen with rituximab) and breast cancer (targeting Her-2/Neu with Herceptin) with complete responses observed in patients with advanced stage disease.
Thus, there is an urgent need for novel therapies that specifically target up-regulated oncogenes such as CEACAM6.